Asymptomatic ulcer in a high-risk patient


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A man aged 52 years man presented with a one-week history of an isolated sore on his upper lip. He reported no recent trauma or antecedent blistering or burning. However, he did admit to a highly risky sex life, boasting about the diversity of his partners.

The man brought documentation of negative HIV and syphilis serologies from four weeks earlier. Physical exam showed a 1-cm indurated, ulcerated nodule on his left upper lip; the ulcer had clean margins and a shallow, pinkish base and was mildly enlarged. Tender lymph nodes were palpable in the left anterior cervical chain. The remainder of the exam was unremarkable. 

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A diagnosis of primary syphilis was made. The history of a single asymptomatic ulcer developing without a prodrome in an individual with high-risk sexual behavior should suggest the diagnosis even before an examination. Although the anatomic location was not typical,...

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A diagnosis of primary syphilis was made. The history of a single asymptomatic ulcer developing without a prodrome in an individual with high-risk sexual behavior should suggest the diagnosis even before an examination. Although the anatomic location was not typical, confirmatory physical clues included the painless ulcer’s induration with clean margins and regional lymphadenopathy. Definitive diagnosis was made with serologic studies.

Syphilis, caused by Treponema pallidum, has been a known sexually transmitted disease (STD) since the 16th century.1 Prior to the era of antibotics, the late effects of tertiary syphilis, aortic dissection, central nervous system damage, and the like were devastating to as many as one third of people infected.2 Although the prevalence and incidence of the disease have dropped dramatically since the 16th century, the incidence has been trending upward over the past decade.2

Syphilis is spread through intimate skin-to-skin contact, most commonly through sexual intercourse; however, the disease may be acquired through oral-genital or mouth-to-mouth contact as well.3 Transmission typically occurs through microscopic mucocutaneous abrasions, although it may occur across intact skin.2T. pallidum is highly sensitive to heat, desiccation, and detergents, so other modes of skin-to-skin transmission are less likely.3 Upon entry, bacteria multiply locally and subsequently disseminate widely via the vascular and lymphatic systems. As early as one week after inoculation T. pallidum can be found in the cornea of the eyes as well as the cerebral spinal fluid.2T. pallidum‘s predilection for small arteries and arterioles causes its characteristic and pathologic inflammatory process, endarteritis obliterans.3

Biopsy of a chancre reveals a variably eroded epidermis overlying a dermal infiltrate containing lymphoid and plasma cells. Capillary endothelial cells demonstrate proliferation and swelling.4 Vascular infiltration by plasma cells and lymphocytes may be present.4 Visualization of T. pallidum requires special staining with either a silver-based stain such as the Warthin-Starry preparation or, more recently, a special immunohistochemical stain.4 Whereas the Warthin-Starry stain is highly insensitive, resulting in many false negatives, the new immunohistochemical stain is highly sensitive and specific.

Untreated, syphilis progresses through several highly individualized stages. Primary syphilis is recognized by the typically asymptomatic, 1- to 2-cm clean-based, indurated ulcer that develops at the site of inoculation within three to six weeks following infection.2 Accompanying regional lymphadenopathy is common. Within six to eight weeks, these findings spontaneously resolve.

Cutaneous findings of secondary syphilis usually occur during the first year of infection (between months 1 and 10) and are highly variable. Perhaps the most typical is a widespread macular and papular, hyperkeratotic eruption that characteristically involves the trunk as well as the palms and soles. Secondary syphilis also remits spontaneously within two months, followed by a latent phase. Syphilis may remain permanently latent; however, up to one third of untreated patients develop at least one clinical manifestation of tertiary syphilis years later.2

Tertiary syphilitic consequences include aortic dissection, coronary artery disease, valvular heart disease, basal meningitis, central nervous damage, and the classic raised, ulcerating subcutaneous lesions known as gummae.

A myriad of diseases may present with an oral/pharyngeal ulcer. Conditions to be considered in the differential include infectious disorders (e.g., herpesviruses , coxsackievirus, and HIV), immune-mediated diseases (e.g., Behcet’s disease, systemic lupus, Crohn’s, celiac disease, and pemphigus vulgaris), and mucocutaneous malignancies. Occurring in only 50% of herpetic lesions, the lack of prodromal symptoms such as tingling or burning cannot automatically exclude the diagnosis of either herpes simplex or varicella.5 Lesion morphology, however, makes these conditions less likely since they typically manifest as clusters of vesiculo-papules before ulceration. The immune-mediated diseases listed generally present with multiple lesions and usually have accompanying symptoms. Lastly, although mucocutaneous malignancies do not erupt over a one-week timeline, they should be considered because definitive surgical intervention is necessary.

A variety of diagnostic tools can be used to diagnosis primary syphilis. T. pallidum can be detected from a chancre via darkfield-microscopy, polymerase chain reaction, Warthin-Starry staining, and direct immunofluorescence. The oral location of a chancre limits the tools somewhat: Dark-field microscopy may give a false-positive test by detecting spirochetes of the normal oral flora; plasma cells are a normal histologic finding of the oral mucosa, so their presence would not be a clue for syphilis. Therefore, the definitive diagnosis with an oral chancre is typically made via serology, which is positive in 80%-90% of primary syphilis cases.

Serologic diagnosis of syphilis involves a two-step process. The initial screening test consists of the highly sensitive—yet nonspecific—nontreponemal tests (i.e., the Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin [RPR]). If the results of these are positive, a confirmatory test—the fluorescent treponemal antibody (FTA), which is specific for anti-treponemal antibodies—is performed. If positive, the diagnosis is confirmed, and the patient should be treated.

The treatment of uncomplicated primary and secondary syphilis in an adult is fairly straightforward. Administration of a single intramuscular (IM) injection of 2.4 million units of long-acting benzathine penicillin G is sufficient for most people.6 Alternatives for those allergic to penicillin include doxycycline 100 mg orally b.i.d. for two weeks, tetracycline 500 mg orally b.i.d. for two weeks, erythromycin 500 mg orally b.i.d. for two weeks, or 250 mg ceftriaxone IM daily for 10 days.7 Patients with early syphilis may develop the Jarisch-Herxheimer ( J-H) reaction in the first 24 hours of treatment. This a systemic inflammatory reaction to the release of massive endotoxins associated with effective antibiotic therapy.2 Common symptoms of the J-H reaction are flulike in nature and includie fever, chills, malaise, headache, nausea, myalgias/arthralgias, and the appearance of a disseminated rash. These symptoms should resolve within 24 hours.

Although treatment of primary and secondary syphilis is straightforward, monitoring patients in the ensuing months can be complicated. One of the nontreponemal antibody tests (VDRL or RPR) should be checked six months after completion of therapy; the titer should be decreased by a factor of four.2 If this has not occurred, re-infection, resistance, or residual disease must be considered, and treatment plans should be altered accordingly. The FTA test should not be repeated, as it will remain positive for the duration of a patient’s lifetime. If a patient develops neurologic signs in the setting of a suboptimal response in serum titer, consider neurosyphilis and perform an appropriate evaluation. Interpretation of serologic tests and titers in patients with immunosuppression—especially HIV—is complex and beyond the scope of this article.

The diagnosis in this patient was made through serologic testing. Although simultaneous testing for HIV was negative, he was sent to the state health department for treatment and evaluation for other STDs. The patient’s oral lesion resolved two weeks after administration of 2.4 mu of benzathine penicillin.

Mr. Watterson is a third-year medical student at Virginia Commonwealth University, in Richmond. Dr. Nunley is professor of dermatology at Medical College of Virginia Hospitals, Virginia Commonwealth University. Neither author has any relationship to disclose relating to the content of this article.

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1. Kiple KF. The History of Disease. In: Porter R, ed. The Cambridge History of Medicine. New York, N.Y.: Cambridge University Press; 2006:35.

2. Lukehart SA. Syphilis. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill Medical; 2008:1038-1046.

3. Morton RS, Kinghorn GR, Kerdel-Vegas F. The Treponematoses. In: Burns T, Breathnach S, Cox N, Griffiths C, eds. Rook’s Textbook of Dermatology. 4th ed. Malden, Mass.: Blackwell Science Ltd.; 1986:839-884.

4. Crowson AN, Magro C, Mihm M, Jr. Treponemal Diseases. In: Elder DE, Elenitsas R, Johnson BL, Jr, Murphy GF, eds. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2005:591-594.

5. Kimberlin DW, Rouse DJ. Clinical practice. Genital herpes. N Engl J Med. 2004;350:1970-1977. 

6. Workowski KA, Berman SM. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006;55(RR-11):1-94.

7. Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med. 1986;104:368-376.

All electronic documents accessed March 15, 2011.

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